While significant study has been directed at understanding the genetic basis of cancer, there is growing vidence that epigenetic mechanisms also play a significant role. Epigenetic mechanisms, such as hromatin modifications and DNA methylation, are stable, long-term (typically heritable) changes in the ranscriptional potential of a cell that are independent of changes in the underlying genomic sequence. These epigenetic modifications can reveal the transcriptional history and key control mechanisms for protein-coding and miRNA genes. T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder of lymphoblasts arising in the T-cell lineage. The major subtype of human T-ALL can be defined by cytogenetic abnormalities and differentiation arrest at different stages of T-cell development. NOTCH1 serves as a unifying target in this model, as activating NOTCHI mutations have now been found in all of the most common subtypes of T-ALL and in more than 50% of all pediatric T-ALL cases. Our central hypothesis is that comparing the genome-wide epigenetic signatures of T-ALL cells to normal T cell precursors will lead to substantial new insights, including the identification of genes that are differentially regulated, as well as putative markers that might lead to early diagnosis and/or improved monitoring of the progress of tumor therapies. We propose to determine the dynamic changes to cell potential using high-quality epigenetic signatures of chromatin modifications and transcriptional potential during mammalian T cell development and leukemogenesis using a NOTCH-induced mouse model (AIM 1) to determine the epigenetic mechanisms involved in progression of the T-cell leukemias. Information gathered using the mouse models will complement epigenetic state of specific subtypes of human T-ALL with defined genetic mutations (TAL1 pos, +/- NOTCH mutations) (AIM 2). The long-range goal of this proposal is to identify the transcriptional history and key epigenetic control mechanisms genome-wide for all protein-coding and miRNA genes during mammalian T cell development and T cell leukemogenesis and thus provide a critical signature of leukemic identity.
T-Acute lymphoblastic leukemia (T-ALL) is characterized by a block in differentiation of T-cell progenitors, and an accumulation of immature lymphoblasts. Together with genetic changes, epigenetic alterations such as aberrant DNA methylation play a role in the molecular pathogenesis of the disease. Identifying the epigenetic mechanisms dysregulated in T-ALLmay lead to new epigenetic biomarkers and therapies.
|Frock, Richard L; Hu, Jiazhi; Meyers, Robin M et al. (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179-86|
|Tepsuporn, Suprawee; Hu, Jiazhi; Gostissa, Monica et al. (2014) Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice. Cancer Immunol Res 2:857-66|
|Anderson, N M; Harrold, I; Mansour, M R et al. (2014) BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 28:1145-8|
|Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20|
|Hu, Jiazhi; Tepsuporn, Suprawee; Meyers, Robin M et al. (2014) Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes. Proc Natl Acad Sci U S A 111:10269-74|
|Anders, Lars; Guenther, Matthew G; Qi, Jun et al. (2014) Genome-wide localization of small molecules. Nat Biotechnol 32:92-6|
|Gutierrez, Alejandro; Pan, Li; Groen, Richard W J et al. (2014) Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J Clin Invest 124:644-55|
|Mansour, Marc R; Abraham, Brian J; Anders, Lars et al. (2014) Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346:1373-7|
|Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46:364-70|
|Gostissa, Monica; Schwer, Bjoern; Chang, Amelia et al. (2014) IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci U S A 111:2644-9|
Showing the most recent 10 out of 44 publications